Delineating, Imaging, and Assessing Pulmonary Fibrosis Remodeling via Collagen Hybridization

Idiopathic pulmonary fibrosis (IPF) is a progressive, life-threatening disease with no early detection, few treatments, and dismal outcomes. Although Collagen overdeposition is a hallmark of lung fibrosis, current research mostly focuses on the cellular aspect, leaving Collagen, particularly its dynamic remodeling (i.e., degradation and turnover), largely unexplored. Here, using a Collagen hybridizing peptide (CHP) that specifically binds unfolded Collagen chains, we reveal vast Collagen denaturation in human IPF lungs and delineate the spatiotemporal progression of Collagen denaturation three-dimensionally within fibrotic lungs in mice. Transcriptomic analyses support that lung Collagen denaturation is strongly associated with up-regulated Collagen catabolism in mice and patients. We thus show that CHP probing differentiates remodeling responses to antifibrotics and highlights the resolution of established fibrosis by agents up-regulating Collagen catabolism. We further develop a radioactive CHP that detects fibrosis in vivo in mice as early as 7 days postlung-injury (Ashcroft score: 2-3) by positron emission tomography (PET) imaging and ex vivo in clinical lung specimens. These findings establish Collagen denaturation as a promising marker of fibrotic remodeling for the investigation, diagnosis, and therapeutic development of pulmonary fibrosis.